Human monoclonal antibodies have been assumed as attractive agents for antagonist effects in many medical applications: anti-toxins, anti-receptor molecules, anti-cytokine reagents to reduce or abolish an inflammatory response, etc.
Hepatitis C virus (HCV) is a major global health problem, with at least 170 million people infected the world over. HCV results in a chronic infection in 75-80% of those initially infected (Houghton 1996). Very likely, immunological factors influence whether the infection will resolve spontaneously or become chronic. The latter will result in a liver inflammation of variable degree, an inflammation that after 10-20 years may result in cirrhosis (20% of chronic cases), and hepatocellular cancer (HCC; approx. 20% of those with cirrhosis) (Houghton 1996). Current pharmaceutical treatment will fail in 60% of the cases (alpha-interferon+Ribavirin). Thus, there is a need for improved therapy.
HCV was discovered in 1989. Scientific studies have been severely hampered by the fact that there is no robust method to propagate the virus in vitro. Thus, substances cannot be tested for the capacity to block infection by the virus (neutralization assay). Similarly, the only animal model available is chimpanzee, also limiting the number of studies possible (by cost, availability of animals, etc.). As a substitute for a neutralisation assay, the inhibition of binding of one of the two envelope proteins (E2) to target cells has been developed. This is called the NOB assay: neutralisation of binding. Recently, a replicon system where a subgenomic portion of the viral genome replicates inside cells (but is not assembled into viral particles) has been developed, and optimized.
As mentioned previously, the immune system may have an important role in determining the course of the infection. Both the cellular immune response, as well as the humoral immune system, have been implicated as important for the outcome of the HCV infection. The relative importance of them is still disputed.
Whether the humoral immune response (i.e. specific B-lymphocytes and antibodies) can interfere with the clinical course of the disease have gained increasing attention over the last years:                1. The kinetics of antibodies to the hypervariable region (HVR) of E2 (one of the envelope glyco proteins) may be important: early occurrence of anti-HVR antibodies correlate with resolution of the acute infection.        2. Polyclonal anti-HCV immunoglobulin preparations given to liver transplanted patients decreased the occurrence of re-infection by HCV from 94% to 54%.        3. Polyclonal anti-HCV given to infected chimpanzees modulated (ameliorated) the course of the infection.        4. Individuals lacking immunoglobulin have a tendency to get a more severe and fast progressing disease compared to immunocompetent individuals.        5. Anti-HCV antibodies (particularly NOB positive antibodies) correlated with protection in vaccination experiments.        
Accordingly, several groups and companies are currently exploring the possibilities of affecting the course of the infection by administration of anti-HCV antibodies, both to already infected and for prophylaxis (Burioni et al., 1998).
The present inventors have already cloned human antibodies to conserved regions of one of the two envelope proteins, E2 (Allander et al., 2000). These antibodies have NOB activity, and a patent application for them has been filed, i.e. WO 9740176. They bind to two or possibly three different regions (epitopes) on E2.
The role of E1 and E2 in the life cycle of the virus is not fully established, nor is the whole process of virus attachment and entry. Still, antibodies to the HVR of E2 can block infection in animals, and so can antibodies to other parts of HCV (most likely E2). Antibodies to E1 elicited by vaccination in chimpanzees correlated with reduced inflammation of the liver (despite constant viral levels in blood); the mechanism for this is unknown (Maertens et al., 2000).
There is currently no report within prior art on human monoclonal antibodies to the E1 protein derived from combinatorial libraries.